Our intention is to continue our investigations of the ileal and renal bile salt active transport systems which were first described by this laboratory. These studies will progress along the following lines: a. Further delineation of the mechanism of the active ileal transport system. b. The physiological and pharmacological effects that inhibitors of these systems may produce. c. The clinical implications arising from pathology of the GI tract with emphasis on pathologies of the ileum. In addition our work during the past four years has been extended to active transport in the liver and metabolic events associated with the biosynthesis of bile salts from cholesterol. Our intentions in these are to: a. Continue our studies of the role of Cytochrome P450 in the rate limiting step of bile salt biosynthesis (7-alpha-cholesterol hydroxylase). b. Continue our studies of our findings of the inverse relationship between enhanced bile salt biosynthesis and decreased levels of hepatic drug metabolizing enzymes. c. Continue our studies of changes in the hepatic cells arising from interrupted enterohepatic circulation of bile salts as they relate to levels of glutathione and other sulfur containing amino acids. These have toxic and pathological implications as such. These findings will be correlated with proposed investigations in patients bearing the similar fault (i.e. interrupted enterohepatic circulation of bile salts).